Revista Brasileira de Psiquiatria. 2015;37:13–20 ß 2015 Associac¸a˜ o Brasileira de Psiquiatria doi:10.1590/1516-4446-2014-1496 ORIGINAL ARTICLE Antidepressant effects of a single dose of ayahuasca in patients with recurrent depression: a preliminary report Fla´via de L. Oso´rio,1,2 Rafael F. Sanches,1,3 Ligia R. Macedo,1 Rafael G. dos Santos,1 Joa˜o P. Maia-de-Oliveira,4 Lauro Wichert-Ana,1 Draulio B. de Araujo,5,6 Jordi Riba,3,7,8,9 Jose´ A. Crippa,1,2 Jaime E. Hallak1,2 1Department of Neurosciences and Behavior, Ribeira˜o Preto Medical School, Universidade de Sa˜o Paulo (USP), Ribeira˜o Preto, SP, Brazil. 2National Science and Technology Institute for Translational Medicine (INCT-TM), Brazil. 3Centre d’Investigacio´ de Medicaments, Servei de Farmacologia Clı´nica, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain. 4Department of Clinical Medicine, Universidade Federal do Rio Grande do Norte (UFRN), Natal, RN, Brazil. 5Hospital Universita´rio Onofre Lopes, UFRN, Natal, RN, Brazil. 6Brain Institute, UFRN, Natal, RN, Brazil. 7Human Experimental Neuropsychopharmacology, Institut de Recerca, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain. 8Department of Pharmacology and Treatment, Universitat Auto`noma de Barcelona, Spain. 9Centro de Investigacio´n Biome´dica en Red de Salud Mental, CIBERSAM, Barcelona, Spain. Objectives: Ayahuasca (AYA), a natural psychedelic brew prepared from Amazonian plants and rich in dimethyltryptamine (DMT) and harmine, causes effects of subjective well-being and may therefore have antidepressant actions. This study sought to evaluate the effects of a single dose of AYA in six volunteers with a current depressive episode. Methods: Open-label trial conducted in an inpatient psychiatric unit. Results: Statistically significant reductions of up to 82% in depressive scores were observed between baseline and 1, 7, and 21 days after AYA administration, as measured on the Hamilton Rating Scale for Depression (HAM-D), the Montgomery-A˚ sberg Depression Rating Scale (MADRS), and the Anxious-Depression subscale of the Brief Psychiatric Rating Scale (BPRS). AYA administration resulted in nonsignificant changes in Young Mania Rating Scale (YMRS) scores and in the thinking disorder subscale of the BPRS, suggesting that AYA does not induce episodes of mania and/or hypomania in patients with mood disorders and that modifications in thought content, which could indicate psychedelic effects, are not essential for mood improvement. Conclusions: These results suggest that AYA has fast-acting anxiolytic and antidepressant effects in patients with a depressive disorder. Keywords: Psychedelic agents; dimethyltryptamine; harmine; monoamine oxidase inhibitors; therapeutic use Introduction low response rates, as well as adverse effects and latency to onset of therapeutic action.3 Thus, new Depression is a highly prevalent disorder and is associated interventions, particularly those that with the potential with intense personal suffering, increased mortality, and for acute effect, would have a huge impact on the 1,2 high morbidity. Although its etiology is unknown, some treatment of depression. The N-methyl-D-aspartate 3 theories suggest that biological factors may be implicated. (NMDA) receptor antagonist ketamine, for example, has One such theory is the monoamine hypothesis, which rapid and potent antidepressant effects in treatment- suggests that an imbalance in cerebral monoamines such resistant major depressive disorder (MDD) and bipolar as dopamine, norepinephrine, and, especially, serotonin is depression, and its use is considered one of the most 3 responsible for depressive symptomatology. The mono- exciting areas in contemporary psychiatric research.4,5 amine hypothesis is the theory on which the leading Ayahuasca (AYA), a botanical hallucinogen tradition- 3 commercially available antidepressants are based. ally used by indigenous groups of the Northwest Amazon Currently available treatments have limitations that can region for ritual and medicinal purposes,6,7 is a potential lead to low therapeutic effectiveness, especially related to candidate for this new generation of antidepressant research focusing on new pharmacological treatments that produce immediate and more pronounced effects. Correspondence: Jaime E. C. Hallak, Departamento de Neurocieˆncias AYA is prepared by prolonged decoction of the bark of the e Cieˆncias do Comportamento, Faculdade de Medicina de Ribeira˜o vine Banisteriopsis caapi with the leaves of the shrub 6 Preto, Universidade de Sa˜o Paulo, Hospital das Clı´nicas, 3 andar, 6,7 b Av. Bandeirantes, 3900, Ribeira˜o Preto, SP, Brazil. Psychotria viridis. B. caapi contains the -carboline E-mail: [email protected] alkaloids harmine, tetrahydroharmine (THH), and harma- Submitted Jun 20 2014, accepted Aug 08 2014. line, which act as monoamine oxidase A inhibitors 14 FL Oso´rio et al. (MAOI), while P. viridis is rich in the psychedelic antidepressants/substance use were considered exclu- tryptamine N, N-dimethyltryptamine (DMT).6,8-11 sion criteria. The psychoactive effects of AYA are produced by a The study was conducted in accordance with the combined action of peripheral (gastrointestinal and liver) Declarations of Helsinki and Tokyo concerning human monoamine oxidase A (MAO-A) inhibition by harmine and subject research and approved by the Research Ethics central 5-HT1A/2A/2C agonist action of DMT on frontal and Committee of Hospital das Clı´nicas da Faculdade de paralimbic brain areas.8,9,12 Studies conducted among Medicina de Ribeira˜o Preto da Universidade de Sa˜o long-term (i.e., years or decades) members of religious Paulo, Ribeira˜o Preto, state of Sa˜o Paulo, Brazil (HC-RP groups that use AYA ritually suggest that this population process no. 2484/2008). The volunteers received detailed does not present evidence of psychological, neuropsy- information on the nature of AYA, the general psycholo- chological, or psychiatric harm caused by AYA.13-15 In gical effects of hallucinogens, and its possible adverse fact, there are several reports describing reduced mental effects, as reported in the psychiatric literature. All volunteers health problems in AYA users.13-15 Nevertheless, given gave their written informed consent to participate. the small number of studies, most with a limited number of participants, there is insufficient information to allow a Drug definitive conclusion on this topic, and more studies on the potential long-term toxicity of AYA are required. We obtained a standard sample of AYA prepared by An increasing number of studies report antidepressive members of the Santo Daime community, consisting of the potential for AYA alkaloids in animals.16-24 Furthermore, stalks of B. caapi (rich in harmine, THH, and harmaline) a double-blind, placebo-controlled animal study reported combined with the washed leaves of P. viridis (rich in reduced hopelessness and panic-related signs after DMT), boiled and concentrated for several hours. The acute AYA administration,25 and preliminary data in resulting brew was stored in plastic bottles at room humans also support an antidepressive action for AYA.26 temperature at the Santo Daime community and sub- The agonist action of AYA alkaloids on serotonergic sequently in a refrigerator in the Department of receptors and its inhibitory effects on MAO-A, associated Neurosciences and Behavior, Ribeira˜o Preto Medical with field and laboratory evidence suggesting that AYA School, Universidade de Sa˜o Paulo, Ribeira˜o Preto, causes a sensation of well-being, led to the hypothesis Brazil. AYA was stored under refrigeration until the day that this substance could be useful in the treatment of of the experimental session. All AYA used in the present depression in humans. Thus, the objective of the present study was from this original batch. preliminary, open-label study was to evaluate the acute Each subject drank 120-200 mL of AYA (2.2 mL/kg effects of a single dose of AYA in patients diagnosed with body weight). The AYA batch used in the experiment depression and to test whether AYA administration could contained 0.8 mg/mL DMT, 0.21 mg/mL harmine, and no produce an acute antidepressant effect. harmaline at the chromatography detection threshold of 0.02 mg/mL. To quantify the content of each alkaloid, a 1-mL sample of AYA was homogenized with sodium Methods acetate buffer solution (pH = 9), extracted with 5 mL Volunteers diethyl ether in a shaker (20 min), and centrifuged at 3,000 rpm for 15 min. The organic phase was collected Six volunteers (two men and four women, mean age and evaporated under a nitrogen stream. The residue 44.16613.55 years) with a diagnosis of recurrent MDD was dissolved in 1 mL methanol and 1 mL of the resulting participated in the study. Within this group, two volunteers solution was analyzed by gas chromatography/mass were experiencing a current mild depressive episode, spectrometry (GC/MS), performed using a Varian three were experiencing a moderate episode, and one CP3800 gas chromatograph coupled to a Varian Saturn was experiencing a severe depressive episode. None of 2000 ion trap mass spectrometer (Varian Inc.). A capillary the volunteers were experiencing depressive episodes column (DB-5MS, 30 m 6 0.25 mm i.d. 6 0.25 mm film with psychotic symptoms. thickness; Agilent) was used. The chromatographic Participants were recruited through local advertise- conditions were as follows: injector temperature 2506C ments and by referrals from private psychiatric clinics. in splitless mode and oven temperature program